EP0849269A1 - Vinyl pyrrolidine cephalosporins with basic substituents - Google Patents

Vinyl pyrrolidine cephalosporins with basic substituents Download PDF

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Publication number
EP0849269A1
EP0849269A1 EP97121833A EP97121833A EP0849269A1 EP 0849269 A1 EP0849269 A1 EP 0849269A1 EP 97121833 A EP97121833 A EP 97121833A EP 97121833 A EP97121833 A EP 97121833A EP 0849269 A1 EP0849269 A1 EP 0849269A1
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Prior art keywords
oxo
hydrogen
formula
amino
carboxylic acid
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EP97121833A
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German (de)
French (fr)
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EP0849269B1 (en
EP0849269B9 (en
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Peter Angehrn
Paul Hebeisen
Ingrid Heinze-Krauss
Malcolm Page
Valérie Runtz
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Basilea Pharmaceutica AG
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to cephalosporin derivatives of the general formula wherein
  • Preferred compounds of formula I are compounds wherein
  • the compounds of the present formula I are useful in the treatment of infectious diseases caused by bacterial pathogens in particular methicillin resistent Staphylococci aureus (MRSA) and Pseudomonas aeruginosa .
  • MRSA methicillin resistent Staphylococci aureus
  • Pseudomonas aeruginosa bacterial pathogens in particular methicillin resistent Staphylococci aureus (MRSA) and Pseudomonas aeruginosa .
  • R 2 substituted pyrrolidinone can be present in the E-form: or in the Z-form:
  • protected amino group refers to groups such as those employed in peptide chemistry, such as an alkoxycarbonyl group such as tert-butoxycarbonyl, allyloxy carbonyl and the like; a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl etc.; an optionally substituted aralkyloxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; an alkanoyl group such as formyl or acetyl; a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl; or a silyl protective group such as the trimethylsilyl group.
  • an alkoxycarbonyl group such as tert-butoxycarbonyl, allyloxy carbonyl and
  • Preferred amino protecting groups are tert-butoxycarbonyl (t-BOC), allyloxycarbonyl (ALLOC) and trityl.
  • alkyl refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
  • ⁇ -hydroxy-alkyl refers to both straight and branched chain saturated hydrocarbon groups as defined above bearing a hydroxy group in the terminal position, e.g. hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
  • ⁇ -amino-alkyl refers to both straight and branched chain saturated hydrocarbon groups as defined above bearing an amino group in the terminal position, e.g. aminomethyl, 2-aminoethyl, 3-aminopropyl, and the like.
  • salts useful in this invention include salts derived from metals, salts from amino acids and salts of mineral or organic acids.
  • preferred metal salts are those derived from the alkali metals, for example, lithium (Li + ), sodium (Na + ) and potassium (K + ), from the earth alkali metals, for example magnesium (Mg ++ ).
  • Those salts derived from amino acids such as, for example, salts with arginine or lysine.
  • salts of mineral acids are for example chlorides, sulphates or phosphates, and examples of salts of organic acids mesylates, napsylates, besylates, maleates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like.
  • chlorides, sulfates, phosphates, lactates or mesylates are especially preferred.
  • esters of the compounds of formula I there are to be understood compounds of formula I, wherein the carboxy group in 2-position is present in the form of readily hydrolyzable ester group.
  • esters which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g.,
  • esters e.g., the benzyl and cyanomethyl esters
  • Other examples of such esters are the following: (2,2-dimethyl-1-oxopropoxy)methyl ester; 2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester; 1-[[(1-methylethoxy)carbonyl]oxy] ethyl ester; 1-(acetyloxy) ethyl ester; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester; 1-[[(cyclohexyloxy)carbonyl]oxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester.
  • the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound.
  • a preferred embodiment of the invention are compounds of formula I wherein X is CH or N and R 2 respresents a group of the formula wherein R 4 is hydrogen, iminomethyl or 1-carbamimidoyl; R 5 is hydrogen or hydroxymethyl; and R 6 is hydrogen or hydroxy.
  • X is CH or N and R 2 represents a group of the formula wherein R 4 , R 5 and R 6 are as defined above.
  • An especially preferred embodiment of the invention are compounds of formula I, wherein X is CH and R 2 is a group of formula wherein R 4 is as defined above.
  • a further especially preferred group of compounds consists of compounds of formula I wherein X is N and R 2 is a group of formula wherein R 4 is as defined above.
  • a further preferred embodiment are compounds of formula I, wherein
  • Such especially preferred compounds are for example
  • the compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated.
  • the hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
  • the compounds of the present invention are useful as antibiotics having potent and broad antibacterial activity; especially against methicillin resistent Staphylococci (MRSA) and Pseudomonas aeruginosa .
  • the products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for parenteral administration, and for this purpose are preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate (e.g. glucose) solution.
  • customary agents such as water or isotonic common salt or carbohydrate (e.g. glucose) solution.
  • the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human.
  • a daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated.
  • the daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.
  • the dose (ip) was 10 mg/kg.
  • the median log of colony forming units (CFU) was determined. A more than hundred-fold reduction in the numer of CFUs was achieved by compound A as compared to the untreated control.
  • the compound A was more active than vancomycin, the standard drug for clinical infections due to MRSA.
  • In vivo efficacy Compound no. mice Median log CFU None 3 6.92 Vancomycin 3 5.28 A 3 4.72
  • reaction of compounds of formula II and III or a reactive derivative of formula III according to embodiment (a) can be carried out in a manner known per se.
  • the carboxy group in compounds of formula II can be protected, for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester), a tert-butyl, allyl, p-methoxybenzyl or a benzhydryl ester.
  • protecting groups R f are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the tertbutoxycarbonyl or trityl groups), by basic hydrolysis (e.g. the trifluoroacetyl group), by hydrazinolysis (e.g. the phthalimido group) or by catalytic cleavage in presence of Pd (the allyloxycarbonyl group).
  • Preferred protecting groups are the allyloxycarbonyl, the tert-butyloxy-carbonyl, the chloroacetyl, bromoacetyl and iodoacetyl groups, especially the chloroacetyl group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea.
  • the 7-amino group in compounds II can be protected, for example, by a silyl protective group such as the trimethylsilyl group.
  • a free carboxylic acid in reacting a 7-amino compound of formula II with a carboxylic acid of formula III or a reactive functional derivative thereof, for example, a free carboxylic acid can be reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and subsequently the ester group can be cleaved off.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide
  • a salt of an acid of formula II e.g. a trialkylammonium salt such as the triethylammonium salt
  • a reactive functional derivative of a carboxylic acid of formula III in an inert solvent (e.g. dimethylformamide or dimethylacetamide).
  • preferred acylation involves the use of a reactive functional derivative of the acylation agent of formula III, for example, a mixed anhydride of thiophosphoric acid of the carboxylic acid, a 1-hydroxybenzotriazole ester or a 2-benzothiazolyl thioester.
  • a mixed anhydride of thiophosphoric acid may be reacted with the compound of formula II preferably in a polar solvent as dimethyl formamide (DMF), dichloromethane, or a mixture of DMF/i-propanol/water in presence of a base as e.g. triethylamine.
  • the 1-hydroxybenzotriazole ester as well as the 2-benzthiazolyl thioester may be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g. methylene chloride, or in dimethylformamide, dimethylacetamide, acetone, ethyl acetate or in a mixture of such solvents with water.
  • an inert organic solvent such as a chlorinated hydrocarbon e.g. methylene chloride, or in dimethylformamide, dimethylacetamide, acetone, ethyl acetate or in a mixture of such solvents with water.
  • a reactive 2-benzthiazolyl thioester is for example this compound is new and is part of the present invention.
  • reaction of a 7-amino compound of formula II with the carboxylic acid of formula III or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.
  • Embodiment (b) of the process of the present invention involves deprotection (removal) of a protected amino group in the 2-position of the thiazol or the thiadiazol ring and /or the protected pyrrolidin ring (R 4 as the protecting group), and/or protected hydroxy or carboxylic groups present in a compound of formula IV and can be carried and as follows:
  • amino protecting groups may be cleaved off by acid hydrolysis (e.g. the tert-butoxycarbonyl or trityl group), e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e.g. the phthalimido group). The allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles. The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved off by treatment with thiourea.
  • acid hydrolysis e.g. the tert-butoxycarbonyl or trityl group
  • aqueous formic acid e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluor
  • Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated.
  • a lower alkanecarboxylic acid which may be halogenated.
  • formic acid or trifluoroacetic acid is used.
  • the reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride.
  • the acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about -30°C to +40°C).
  • Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C.
  • the chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C.
  • hydroxy protecting group refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilyl, tert.-butyl-dimethylsilyl, dimethylphenylsilyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl and the like.
  • carboxylic acid protecting group refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid.
  • carboxyl protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, for example, methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, i-propyl-dimethylsilyl.
  • Preferred are benzyhydryl, tert-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.

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Abstract

The present invention relates to cephalosporin derivatives of the general formula
Figure 80000001
wherein
X
is CH or N;
R1
is hydrogen or cyclopentyl;
R2
is a group of formula
Figure 80000002
R3
is hydrogen, an alkalimetal ion or a tertiary ammonium group;
R4
is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl;
R5
is hydrogen, dialkylcarbamoyl, ω-hydroxyalkyl, ω-aminoalkyl, pyridinium-1-ylmethyl, 1-hydroxy-3-aminomethyl-propyl or (hydroxy)-(pyrrolidin-2-yl)methyl;
R6
is hydrogen, trifluoromethyl or hydroxy; and
R7
is alkyl, ω-hydroxy-alkyl, cycloalkyl, 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl;
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts;
the invention is further concerned with the manufacture of compounds of formula I; with their use as pharmaceutically active substances,
particularly for the treatment and prophylaxis of infectious diseases, and with pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases.

Description

The present invention relates to cephalosporin derivatives of the general formula
Figure 00010001
   wherein
X
is CH or N;
R1
is hydrogen or cyclopentyl;
R2
is a group of formula
Figure 00010002
Figure 00020001
R3
is hydrogen, an alkalimetal ion or a tertiary ammonium group;
R4
is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl;
R5
is hydrogen, dialkylcarbamoyl, ω-hydroxyalkyl, ω-aminoalkyl, pyridinium-1-ylmethyl, 1-hydroxy-3-aminomethyl-propyl or (hydroxy)-(pyrrolidin-2-yl)methyl;
R6
is hydrogen, trifluoromethyl or hydroxy; and
R7
is alkyl, ω-hydroxy-alkyl, cycloalkyl, 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl;
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
Furthermore, the invention is concerned with the manufacture of compounds of formula I; with their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases, and with pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by methicillin resistent Staphylococcus aureus (MRSA).
Preferred compounds of formula I are compounds wherein
X
is CH or N;
R1
is hydrogen;
R2
is a group of formula
Figure 00020002
Figure 00030001
R3
is hydrogen, an alkalimetal ion or a tertiary ammonium group;
R4
is hydrogen, an amino protecting group, iminomethyl, or 1-carbamimidoyl;
R5
is hydrogen, hydroxymethyl;
R6
is hydrogen or hydroxy; and
R7
methyl or 2-hydroxyethyl;
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
The compounds of the present formula I are useful in the treatment of infectious diseases caused by bacterial pathogens in particular methicillin resistent Staphylococci aureus (MRSA) and Pseudomonas aeruginosa.
In above compounds of formula I the R2 substituted pyrrolidinone can be present
Figure 00030002
in the E-form:
Figure 00030003
or in the Z-form:
Compounds of formula Ia, i.e. compounds wherein the pyrrolidinone is in the E-form are generally preferred.
The term "protected amino group" refers to groups such as those employed in peptide chemistry, such as an alkoxycarbonyl group such as tert-butoxycarbonyl, allyloxy carbonyl and the like; a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl etc.; an optionally substituted aralkyloxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; an alkanoyl group such as formyl or acetyl; a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl; or a silyl protective group such as the trimethylsilyl group.
Preferred amino protecting groups are tert-butoxycarbonyl (t-BOC), allyloxycarbonyl (ALLOC) and trityl.
As used herein, the term "alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
As used herein, the term "ω-hydroxy-alkyl" refers to both straight and branched chain saturated hydrocarbon groups as defined above bearing a hydroxy group in the terminal position, e.g. hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
As used herein, the term "ω-amino-alkyl" refers to both straight and branched chain saturated hydrocarbon groups as defined above bearing an amino group in the terminal position, e.g. aminomethyl, 2-aminoethyl, 3-aminopropyl, and the like.
As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, salts from amino acids and salts of mineral or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li+), sodium (Na+) and potassium (K+), from the earth alkali metals, for example magnesium (Mg++). Those salts derived from amino acids such as, for example, salts with arginine or lysine. Examples of salts of mineral acids are for example chlorides, sulphates or phosphates, and examples of salts of organic acids mesylates, napsylates, besylates, maleates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like. Especially preferred are chlorides, sulfates, phosphates, lactates or mesylates.
As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, wherein the carboxy group in 2-position is present in the form of readily hydrolyzable ester group. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g., the acetamidomethyl ester). Other esters (e.g., the benzyl and cyanomethyl esters) can also be used. Other examples of such esters are the following: (2,2-dimethyl-1-oxopropoxy)methyl ester; 2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester; 1-[[(1-methylethoxy)carbonyl]oxy] ethyl ester; 1-(acetyloxy) ethyl ester; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester; 1-[[(cyclohexyloxy)carbonyl]oxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester. It will be appreciated by those of ordinary skill in the art that the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound.
Examples of salts of the compounds of formula I are defined under "pharmaceutically acceptable salts" above.
A preferred embodiment of the invention are compounds of formula I wherein X is CH or N and R2 respresents a group of the formula
Figure 00050001
   wherein R4 is hydrogen, iminomethyl or 1-carbamimidoyl; R5 is hydrogen or hydroxymethyl; and R6 is hydrogen or hydroxy.
In a further preferred embodiment of the compounds of formula I X is CH or N and R2 represents a group of the formula
Figure 00050002
   wherein R4, R5 and R6 are as defined above.
Especially preferred are compounds of formula I wherein R5 and R6 are hydrogen.
An especially preferred embodiment of the invention are compounds of formula I, wherein X is CH and R2 is a group of formula
Figure 00060001
   wherein R4 is as defined above.
A further especially preferred group of compounds consists of compounds of formula I wherein X is N and R2 is a group of formula
Figure 00060002
   wherein R4 is as defined above.
A further preferred embodiment are compounds of formula I, wherein
X
is CH or N
R1
is hydrogen or cyclopentyl
R2
is a group of formula
Figure 00060003
R3
is hydrogen, an alkalimetal ion or a tertiary ammonium group,
R4
is hydrogen, an amino protecting group;
R5
is hydrogen, dialkylcarbamoyl, and
R6
is hydrogen or trifluoromethyl,
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
Such especially preferred compounds are for example
  • A: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00070001
  • B: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00070002
  • C: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1'-iminomethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00070003
  • D: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-( (R)-1'-carbamimidoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00080001
  • E: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00080002
  • F: (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5'-hydroxymethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00080003
    • The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
    The compounds of the present invention are useful as antibiotics having potent and broad antibacterial activity; especially against methicillin resistent Staphylococci (MRSA) and Pseudomonas aeruginosa.
    The products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for parenteral administration, and for this purpose are preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate (e.g. glucose) solution.
    Depending on the nature of the pharmacologically active compound the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human. A daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated. The daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.
    Representative compounds (A and B, above) of the present invention were tested. In vitro activity was determined by minimum inhibitory concentration by the agar dilution method in Mueller Hinton agar, inoculum = 104 CFU/spot.
    In vitro activity (MIC [µg/ml])
    A B
    MIC S.aureus 6538 (MSSA) 0.5 0.25
    MIC S. aureus 743 (MRSA) 2 2
    MIC S. aureus 270A (MRSA) 2 4
    MIC90 (MRSA, n=38) 4 4
    MIC P. aeruginosa ATCC27853 2 4
    In vivo efficacy was determined with a sc abscess model in mice, infected with S. aureus 270 A (MRSA). The dose (ip) was 10 mg/kg. The median log of colony forming units (CFU) was determined. A more than hundred-fold reduction in the numer of CFUs was achieved by compound A as compared to the untreated control. The compound A was more active than vancomycin, the standard drug for clinical infections due to MRSA.
    In vivo efficacy
    Compound no. mice Median log CFU
    None 3 6.92
    Vancomycin 3 5.28
    A 3 4.72
    The compounds of the formula I in accordance with the invention as well as their pharmaceutical acceptable salts, hydrates, or readily hydrolyzable esters can be manufactured in accordance with the invention for example by
  • (a) treating a compound having the formula II
    Figure 00100001
       wherein R2 is defined as above, or an ester or a salt thereof, the amino group and the carboxylic groups present in the compound of formula II may be unprotected or protected,
    with a carboxylic acid of the general formula III
    Figure 00100002
       in which Rf is hydrogen or an amino protecting group, R1' is hydrogen, cyclopentyl or a hydroxy protecting group and X is as defined above, or with a reactive functional derivative thereof, or
  • (b) cleaving off the amino, hydroxy and/or carboxy protecting group in a compound having the formula IV
    Figure 00110001
    in which R2 is as defined above, Rf is hydrogen or an amino protecting group, R1'' is hydrogen or a hydroxy protecting group, Rh is hydrogen or a carboxy protecting group, provided that at least one of Rf, R1'' and Rh is a corresponding protecting group,
    or a salt thereof.
    • The reaction of compounds of formula II and III or a reactive derivative of formula III according to embodiment (a) can be carried out in a manner known per se. The carboxy group in compounds of formula II can be protected, for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester), a tert-butyl, allyl, p-methoxybenzyl or a benzhydryl ester.
    The amino group present in the acylating agent of formula III can be protected. Possible protecting groups Rf are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the tertbutoxycarbonyl or trityl groups), by basic hydrolysis (e.g. the trifluoroacetyl group), by hydrazinolysis (e.g. the phthalimido group) or by catalytic cleavage in presence of Pd (the allyloxycarbonyl group). Preferred protecting groups are the allyloxycarbonyl, the tert-butyloxy-carbonyl, the chloroacetyl, bromoacetyl and iodoacetyl groups, especially the chloroacetyl group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea. The 7-amino group in compounds II can be protected, for example, by a silyl protective group such as the trimethylsilyl group.
    In reacting a 7-amino compound of formula II with a carboxylic acid of formula III or a reactive functional derivative thereof, for example, a free carboxylic acid can be reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and subsequently the ester group can be cleaved off.
    According to another embodiment, a salt of an acid of formula II (e.g. a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of a carboxylic acid of formula III in an inert solvent (e.g. dimethylformamide or dimethylacetamide).
    According to a further embodiment, preferred acylation, where the amino group present in the acylating agent of formula III need not be protected, involves the use of a reactive functional derivative of the acylation agent of formula III, for example, a mixed anhydride of thiophosphoric acid of the carboxylic acid, a 1-hydroxybenzotriazole ester or a 2-benzothiazolyl thioester. For instance, a mixed anhydride of thiophosphoric acid may be reacted with the compound of formula II preferably in a polar solvent as dimethyl formamide (DMF), dichloromethane, or a mixture of DMF/i-propanol/water in presence of a base as e.g. triethylamine. The 1-hydroxybenzotriazole ester as well as the 2-benzthiazolyl thioester may be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g. methylene chloride, or in dimethylformamide, dimethylacetamide, acetone, ethyl acetate or in a mixture of such solvents with water. Such a reactive 2-benzthiazolyl thioester is for example
    Figure 00120001
       this compound is new and is part of the present invention.
    The reaction of a 7-amino compound of formula II with the carboxylic acid of formula III or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.
    Embodiment (b) of the process of the present invention involves deprotection (removal) of a protected amino group in the 2-position of the thiazol or the thiadiazol ring and /or the protected pyrrolidin ring (R4 as the protecting group), and/or protected hydroxy or carboxylic groups present in a compound of formula IV and can be carried and as follows:
    Removal of amino protecting groups
    As mentioned above the amino protecting groups may be cleaved off by acid hydrolysis (e.g. the tert-butoxycarbonyl or trityl group), e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e.g. the phthalimido group). The allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles. The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved off by treatment with thiourea.
    Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about -30°C to +40°C). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C.
    Removal of hydroxy protecting groups
    The term "hydroxy protecting group" refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilyl, tert.-butyl-dimethylsilyl, dimethylphenylsilyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl and the like.
    Preferred hydroxy protecting groups are such as are commonly known in the art, e.g. for protection of hydroxyimino groups (R1 = hydrogen in compounds of formula I), usually trityl, lower alkanoyl, especially acetyl, tetrahydropyranyl.
    These protecting groups are e.g. removed as follows:
    -trityl
    in acidic solvents like 90% formic acid at about 0 to 50°C or triethylsilane in trifluoroacetic acid at about -20 to 25°C;
    in organic solutions of hydrochloric acid at about -50 to 25°C;
    -acetyl
    with weak inorganic bases like sodium bicarbonate in methanol or ethanol/water at about 0 to 50°C;
    -tetrahydropyranyl
    with weak organic acids like p-toluenesulfonic acid in an alcohol, e.g. ethanol, at about 0°C to the boiling point of the mixture.
    Removal of protecting groups at the carboxy function
    The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. As carboxyl protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, for example, methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, i-propyl-dimethylsilyl. Preferred are benzyhydryl, tert-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
    These protecting groups may be removed as follows:
    benzhydryl
    trifluoroacetic acid with anisol, phenol, cresol or triethylsilane at about -40°C to room temperature; hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; BF3-etherate in acetic acid at about 0 to 50°C;
    tert-butyl
    formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about -10°C to room temperature;
    p-nitrobenzyl
    sodium sulfide in acetone/water at about 0 to room temperature; or hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran;
    p-methoxybenzyl
    formic acid at about 0 to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about -40°C to room temperature;
    allyl
    palladium(O) catalyzed transalkylation reaction in the presence of tri-n-butyltinhydride and acetic acid, see for example F. Guibé et al. in J. Org. Chem. (1987) 52, 4984-4993
    Further methods for the manufacture of the compounds according to the invention are known in the art. Compounds of formula I can for example be manufactured in analogy to the methods described in US pat. no. 5 523400 and according to the examples given below.
    Examples Example 1 Preparation of the acylation agent (Z)-(5-Amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester
    Figure 00150001
    To a suspension of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium salt (1.89 g, 3.4 mmol) in 25 ml acetonitrile were added at 0°C 2,2
    Figure 00150002
    -dithio-bisbenzothiazole (1.36 g, 4.1 mmol). A solution of triethylphosphite (0.7 ml, 5.8 mmol) in 7 ml acetonitrile was added within 40 min and the mixture was stirred at room temperature for 27 h. The precipitate was collected by filtration and washed with acetonitrile and n-hexane.
  • Yield: 1.615 g (82%) beige crystals
  • IR(KBr) 1704, 1619, 1003 cm-1
  • MS(ISP) 580.2 (M+H)+.
    • Example 2
  • 2.1. Preparation of a mixture of (1R,3'R)- and (1S,3'R)-3-bromo-2-oxo-[1,3']bipyrrolidinyl-1'-carboxylic acid allyl ester
    Figure 00150003
    A solution of (R)-3-amino-pyrrolidine-1-carboxylic acid allyl ester trifluoroacetate (1 : 3.2) (47.84 g, 0.089 mol) in 180 ml dichloromethane was treated with 50% aqueous sodium hydroxide solution (72 ml, 0.894 mol). To the vigorously stirred mixture was added within 18 min at 0°C a solution of 2-bromo-4-chloro-butanoyl chloride (21.62 g, 0.098 mol) in 90 ml dichloromethane. The reaction mixture was stirred at 0°C for 1 h. The phases were separated, the aqueous phase was extracted twice with 100 ml dichloromethane and the combined organic phases were washed twice with 50 ml water. They were dried over magnesium sulfate and the solvent was removed by evaporation. The residual yellow oil (32 g) was redissolved in 380 ml dichloromethane and 190 ml of a 50% aqueous sodium hydroxide solution and 3.23 g Dowex 2x10 were added with vigorous stirring at room temperature. After 6 h, the phases were separated, the aqueous phase was extracted twice with 150 ml dichloromethane. The combined organic phases were washed once with 100 ml water, once with brine, were dried over magnesium sulfate and concentrated. Yield: 28.7 g (quant.) of a yellow oil
  • IR(neat) 1697cm-1
  • MS(ISP) 317.2 (M)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 2.2. Mixture of (1R,3'S) and (1S,3'S)-3-bromo-2-oxo-[1,3']bipyrrolidinyl-1'-carboxylic acid allyl ester
  • IR(neat) 1697 cm-1
  • MS(ISP) 317.1 (M)+.
  • 2.3. Mixture of (3RS,3'RS)- and (3RS,3'SR)-3-bromo-2-oxo-[1,3']bipyrrolidinyl-1'-carboxylic acid allyl ester
  • IR(neat) 1695 cm-1
  • MS(EI) 259 (M-OC3H5).
  • 2.4. (RS)-3-(3-Bromo-2-oxo-pyrrolidin-1-yl)-azetidine-1-carboxylic acid allyl ester
  • IR(neat) 1700 cm-1
  • MS(ISP) 303.2 (M)+.
  • 2.5. (RS)-4-(3-Bromo-2-oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid allylester
  • IR(neat) 1699 cm-1
  • MS(ISP) 345.2 (M)+.
  • 2.6. (RS)-4-(3-Bromo-2-oxo-pyrrolidin-1-yl)-pyrazolidine-1,2-dicarboxylic acid diallyl ester
  • IR(KBr) 1704 cm-1
  • MS(ISP) 404 (M+H)+.
  • 2.7. 1:1 Mixture of (3S,4R)-3-[(R)- and -[(S)-3-bromo-2-oxo-pyrrolidin-1-ylmethyl]-4-trifluoromethyl-pyrrolidine-1-carboxylic acid allyl ester
  • IR(KBr) 1702 cm-1
  • MS(ISP) 401.3 (M+H)+.
  • 2.8. Mixture of (3R,3'S,5'S)- and (3S,3'S,5'S)-3-bromo-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-1'-carboxylic acid allyl ester
  • IR(KBr) 1699, 1649 cm-1
  • MS(EI) 388 (M+H)+.
  • 2.9. 1:1 Mixture of (3R,3'S,5'R)- and (3S,3'S,5R)-3-bromo-5'-dimethylcarbamoyl-2-oxo-[1,3]bipyrrolidinyl-1'-carboxylic acid allyl ester
  • IR(KBr) 1698, 1654 cm-1
  • MS(ISP) 388.1 (M+H)+.
  • 2.10. (RS)-3-(3-Bromo-2-oxo-pyrrolidin-1-ylmethyl)-azetidine-1-carboxylic acid allyl ester
  • IR(KBr) 1698 cm-1
  • MS(ISP) 319.2 (M+H)+.
    • Example 3
  • 3.1. Mixture of (1R,3'R) and (1S,3'R)-(1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide
    Figure 00170001
    Triphenylphosphine (23.62 g, 0.090 mol) and a mixture of (1R,3'R)- and (1S,3'R)-3-bromo-2-oxo-[1,3']bipyrrolidinyl-1'-carboxylic acid allyl ester (28.56 g, 0.090 mol) were disolved in 80 ml dichloromethane. The solvent was removed in vacuo and the residual oil was heated for 2 h at 100°C. The resulting solid was dissolved in 130 ml dichloromethane and added with stirring to 1500 ml n-hexane resulting in the separation of the product. The solvent was decanted and the residue triturated with 1500 ml diethylether. The thereby formed solid was collected by filtration, washed with n-hexane and diethylether and dried in vacuo, yielding 45.1 g (78%) of the product as colourless crystals.
  • IR(KBr) 1682 cm-1
  • MS(ISP) 499.3 (M)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 3.2. Mixture of (3R,3'S) and (3S,3'S)-(1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide
  • IR(KBr) 1684 cm-1
  • MS(ISP) 499.2 (M)+.
  • 3.3. Mixture of (3RS,3'RS)- and (3RS,3'SR)-(1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide
  • IR(KBr) 1684 cm-1
  • MS(ISP) 499.4 (M+H)+.
  • 3.4. (RS)-[1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide
  • IR(KBr) 1687 cm-1
  • MS(ISP) 485.4 (M+H)+.
  • 3.5. (RS)-[1-(1-Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide
  • IR(KBr) 1688 cm-1
  • MS(ISP) 527.3 (M)+.
  • 3.6. (RS)-[1-(1,2-Bis-allyloxycarbonyl-pyrazolidin-4-yl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide
  • IR(KBr) 1688 cm-1
  • MS(ISP) 585.5 (H)+.
  • 3.7. 1:1 Mixture of [(R)- and [(S)-1-[(S)-1-allyloxycarbonyl-pyrrolidin-2-ylmethyl]-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide
  • IR(KBr) 1682 cm-1
  • MS(ISP) 513.4 (M)+.
  • 3.8. 1:1 Mixture of (3S,4R)-[(R)- and -[(S)-1-(1-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide
  • IR(KBr) 1690 cm-1
  • MS(ISP) 581.2 (M+H)+.
  • 3.9. 1:1 Mixture of (3R,3'S,5'S)- and (3S,3'S,5'S)-(1'-allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide
  • IR(KBr) 1687 cm-1
  • MS(ISP) 570.3 (M)+.
  • 3.10. 1:1 Mixture of (3R,3'S,5'R)- and (3S,3'R,5'S)-3-(1'-allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide
  • IR(KBr) 1686 cm-1
  • MS(ISP) 570.3 (M)+.
  • 3.11. (RS)-[1-(1-Allyloxycarbonyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphonium bromide (1:1)
  • IR(KBr) 1679 cm-1
  • MS(ISP) 499.2 (M)+.
    • Example 4
  • 4.1. (E)-(2R,6R,7R)-3-[(R)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
    Figure 00190001
    A suspension of the mixture of (1R,3'R) and (1S,3'R)-(1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide (43.5 g, 0.075 mol) and (2R,6R,7R)-tert-butoxycarbonylamino-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester (33.74 g, 0.068 mol) in 950 ml butylenoxide was refluxed for 1.5 h. The solvent was removed in vacuo and the residue was purified by column chromatography (300 g SiO2, ethyl acetate : n-hexane = 2:1, 3:1) giving 67.8 g of a 1:1 (molar ratio) mixture containing the product and triphenylphosphine oxide as a yellow foam. Further purification was not necessary to proceed with the next step.
  • IR(KBr) 1781, 1744 cm-1
  • MS(ISP) 732.5 (M+NH4)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 4.2. (E)-(2R,6R,7R)-3-[(S)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1782, 1744, 1705 cm-1
  • MS(ISP) 732.4 (M+NH4)+.
  • 4.3. Mixture of (E)-(2R,6R,7R)-3-[(R)- and -[(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1780, 1744, 1704 cm-1
  • MS(ISP) 715.4 (M+H)+.
  • 4.4. (E)-(2R,6R,7R)-3-[1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1782, 1743, 1713 cm-1
  • MS(ISP) 718.4 (M+NH4)+.
  • 4.5. (E)-(2R,6R,7R)-3-[1-(1-Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1779, 1743, 1692 cm-1
  • MS(ISP) 760.5 (M+NH4)+.
  • 4.6. (E)-(2R,6R,7R)-3-[1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1782, 1711 cm-1
  • MS(ISP) 797.0 (M+H)+.
    • Example 5
  • 5.1. 1:1 Mixture of (E)-(5R,6R,7R)- and-(5S,6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
    Figure 00200001
    A solution of the mixture described above of (E)-(2R,6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester and triphenylphosphine oxide (67.8 g, 0.068 mol) in 400 ml dichloromethane was cooled to -10°C. To this was added dropwise a solution of m-chloroperbenzoic acid (70%, 16.82 g, 0.068 mol) in 250 ml dichloromethane. The resulting solution was stirred for 2.5 h at -5 to 0°C,150 ml aqueous sodium thiosulfate solution (5%) was added and the mixture was stirred for 15 min. The phases were separated and the aqueous phase was extracted twice with 100 ml dichloromethane. The combined organic phase were washed with each 150 ml of aqueous solutions of sodium thiosulfate (5%), sodium bicarbonate (5%) and finally brine. The solution was dried over magnesium sulfate, concentrated after filtration and purified by column chromatography (1000 g SiO2, ethyl acetate : n-hexane = 3 : 1, 1 : 0 and ethyl acetate : methanol = 9 : 1).
  • Yield: 36.3 (73%)
  • IR(KBr) 1797, 1711 cm-1
  • MS(ISP) 748.5 (M+NH4)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 5.2. Mixture of (E)-(5R,6R,7R)- and-(5S,6R,7R)-3-[(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1796, 1710 cm-1
  • MS(ISP) 748.5 (M+NH4)+.
  • 5.3. Mixture of (E)-(5R,6R,7R)- and -(5S,6R,7R)-3-(1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-7-tert.-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (config.at C3' in bipyrrolidine-moeity R and S)
  • IR(KBr) 1796, 1716 cm-1
  • MS(ISP) 748.5 (M+NH4)+.
  • 5.4. Mixture of (E)-(5R,6R,7R)- and -(5S,6R,7R)-3-[1-(1-allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1797, 1718 cm-1
  • MS(ISP) 734.5 (M+NH4)+.
  • 5.5. 1:1 Mixture of (E)-(5R,6R,7R)-and (5S,6R,7R)-3-[1-(1-allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxy carbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add benzhydryl ester
  • IR(KBr) 1795, 1721, 1692 cm-1
  • MS(ISP) 776.5 (M+NH4)+.
  • 5.6. Mixture of (E)-(5R,6R,7R)- and -(5S,6R,7R)-3-[1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1796, 1716 cm-1
  • MS(ISP) 813.4 (M+H)+.
    • Example 6
  • 6.1. (E)-(6R,7R)-3-[(R)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
    Figure 00220001
    To a solution of a mixture of a 1:1 mixture of (E)-(5R,6R,7R)- and-(5S,6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (36.3 g, 0.050 mol) in 370 ml dichloromethane, 30 ml DMF and 44 ml N-methylacetamide was added within 20 min at -30°C a solution of phosphorous tribromide (19.1 ml, 0.203 mol) in 56 ml dichloromethane. After stirring for 1.5 h at -30°C, the mixture was allowed to warm up to -5°C and quenched with 800 ml cold water. The phases were separated, the aqueous phase was extracted twice with 300 ml dichloromethane. The combined organic phases were washed with 500 ml water and brine and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was treated with a 1:1 mixture of ethyl acetate and n-hexane (700 ml). The precipitated product was collected by filtration. Yield: 32.9 g (91%) orange crystals.
  • IR(KBr) 1785, 1715 cm-1
  • MS(ISP) 732.5 (M+NH4)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 6.2. (E)-(6R,7R)-3-[(S)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1786, 1712 cm-1
  • MS(ISP) 732.5 (M+NH4)+.
  • 6.3. Mixture of (E)-(6R,7R)-3-[(R)- and -[(S)-1'-allyloxycarbonyl-2-oxo- [1,3']-bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1785, 1712 cm-1
  • MS(ISP) 732.6 (M+NH4)+.
  • 6.4. (E)-(6R,7R)-3-[1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1786, 1717 cm-1
  • MS(ISP) 718.6 (M+NH4)+.
  • 6.5. (E)-(6R,7R)-3-[1-(1-Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1784, 1688 cm-1
  • MS(ISP) 760.6 (M+NH4)+.
  • 6.6. (E)-(6R,7R)-4-[3-(2-Benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-3-ylmethylene)-2-oxo-pyrrolidin-1-yl]-pyrazolidine-1,2-dicarboxylic acid diallyl ester
  • IR(KBr) 1785 cm-1
  • MS(ISP) 800.6 (M+H)+.
  • 6.7. (E)-(6R,7R)-3-[1-[(S)-1-Allyloxycarbonyl-pyrrolidin-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1784 cm-1
  • MS(ISP) 729.3 (M+H)+.
  • 6.8. (E)-(6R,7R)-3-[1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1790, 1713 cm-1
  • MS(ISP) 797.4 (M+H)+.
  • 6.9. (E)-(6R,7R)-3-[(3'S,5'S)-1'-Allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1787, 1713 cm-1
  • MS(ISP) 786.4 (M+H)+.
  • 6.10. (E)-(6R,7R)-3-[(3'S,5'R)-1'-Allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1786, 1712 cm-1
  • MS(ISP) 786.5 (M+H)+.
  • 6.11. (E)-(6R,7R)-3-[1-(1-Allyloxycarbonyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
  • IR(KBr) 1780, 1700 cm-1
  • MS(ISP) 715.3 (M+H)+.
    • Example 7
  • 7.1. (E)-(6R,7R)-3-[(R)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethy)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
    Figure 00240001
    To a solution of (E)-(6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (32.9 g, 0.046 mol) in 320 ml dichloromethane was added at 0°C 32 ml anisol and 180 ml trifluoroacetic acid. The mixture was stirred for 2.5 h stirring at room temperature, concentrated to a volume of 50 ml and poured on 1000 ml ice-cold diethylether. The precipitated solid was collected by filtration and dried. Yield: 24.9 g (98%) beige solid
  • IR(KBr) 1782, 1680 cm-1
  • MS(ISP) 466.4 (M+NH4)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 7.2. (E)-(6R,7R)-3-[(S)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethy]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
  • IR(KBr) 1782, 1679 cm-1
  • MS(ISP) 466.3 (M+NH4)+.
  • 7.3. Mixture of (E)-(6R,7R)-3-[(R)- and -[(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
  • IR(KBr) 1783, 1678 cm-1
  • MS(ISP) 449.5 (M+H)+.
  • 7.4. (E)-(6R,7R)-3-[1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
  • IR(KBr) 1783, 1681 cm-1
  • MS(ISP) 435.5 (M+H)+.
  • 7.5. (E)-(6R,7R)-3-[1-(1-Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
  • IR(KBr) 1784, 1681 cm-1
  • MS(ISN) 492.3 (M-H+NH3)-.
  • 7.6. (E)-(6R,7R)-7-Amino-3-[1-(1,2-bis-allyoxycarbonyl-pyrazolidin-4-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • m.p. 148-149°C
  • 7.7. (E)-(6R,7R)-3-[1-[(S)-1-Allyloxycarbonyl-pyrrolidin-2-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (1:0.2)
  • IR(KBr) 1780, 1690 cm-1
  • MS(ISP) 463.3 (M+H)+.
  • 7.8. (E)-(6R,7R)-3-[1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1779, 1686 cm-1
  • MS(ISP) 531.3 (M+H)+.
  • 7.9. (E)-(6R,7R)-3-[(3'S,5'S)-1'-Allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (1:0.4)
  • IR(KBr) 1779, 1681 cm-1
  • MS(ISP) 520.2 (M+H)+.
  • 7.10. (E)-(6R,7R)-3-[(3'S,5'R)-1'-Allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (1:0.5)
  • IR(KBr) 1779, 1681 cm-1
  • MS(ISP) 520.3 (M+H)+.
    • Example 8
  • 8.1. (6R,7R)-3-[(E)-(R)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00260001
    A solution of (E)-(6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethy)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (3.90 g, 7.06 mmol) ) in 75 ml DMF was treated with (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester (4.5 g, 7.76 mmol) for 48 h at room temperature. The reaction mixture was concentrated in vacuo and the residue distributed between 550 ml ethyl acetate and 375 ml water. The solid was discarded, the phases were separated and the aqueous phase was extracted with 150 ml ethyl acetate. The combined organic phases were concentrated upon which the product separated. It was collected by filtration, washed with ethyl acetate and dried.
  • Yield: 4.42 g (68%) beige crystals
  • IR(KBr) 1785, 1681 cm-1
  • MS(ISP) 878.6 (M+NH4)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 8.2. (6R,7R)-3-[(E)-(S)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1784, 1680 cm-1
  • MS(ISP) 878.6 (M+NH4)+.
  • 8.3. Mixture of (6R,7R)-3-[(E)-(R)- and -(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1783, 1681 cm-1
  • MS(ISP) 861.5 (M+H)+.
  • 8.4. (6R,7R)-3-[(E)-1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1784, 1683 cm-1
  • MS(ISP) 864.3 (M+NH4)+.
  • 8.5. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[(E)-1-(1,2-bis-allyloxycarbonyl-pyrazolidin-4-yl)-3-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • m.p. 184-185°C
  • MS(ISP) 946.1 (M+H)+.
  • 8.6. (6R,7R)-3-[(E)-1-[(S)-1-Allyloxycarbonyl-pyrrolidin-2-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1790, 1681 cm-1
  • MS(ISP) 875.4 (M+H)+.
  • 8.7. (6R,7R)-3-[(E)-1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(5-amino[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1790, 1687 cm-1
  • MS(ISP) 943.7 (M+H)+.
    • Example 9
  • 9.1. Mixture of (6R,7R)-3-[(E)-(R)- and -(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00280001
    A solution of (E)-(6R,7R)-3-[(R)- and [(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (721 mg, 1.3 mmol) in 25 ml DMF was treated with (Z)-(2-aminothiazol-4-yl)-trityloxyimino-acetic acid 1-benzotriazolyl ester (782 mg, 1.43 mmol) at room temperature for 36 h. The reaction mixture was concentrated in vacuo and the residue distributed between 100 ml ethyl acetate and 50 ml water. The insoluble material was removed by filtration, the phases were separated and the organic phase was concentrated upon which the product precipitated. The solid was collected by filtration, washed with ethyl acetate and dried.
  • Yield: 725 mg (60%)
  • IR(KBr) 1783, 1681 cm-1
  • MS(ISP) 860.6 (M+H)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 9.2. (6R,7R)-3-[(E)-(R)-1'-Allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1783, 1679 cm-1
  • MS(ISP) 860.5 (M+H)+.
  • 9.3. (6R,7R)-3-[(E)-1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1785, 1680 cm-1
  • MS(ISP) 846.6 (M+H)+.
  • 9.4. (6R,7R)-3-[(E)-1-(Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1782, 1673 cm-1
  • MS(ISP) 888.5 (M)+.
  • 9.5. (6R,7R)-3-[(E)-1-(1,2-bis-allyoxycarbonyl-pyrazolidin-4-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1756 cm-1
  • MS(ISP) 536.3 (M+H)+.
  • 9.6. (6R,7R)-3-[(E)-1-[(3S,4R)-1-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1790, 1686 cm-1
  • MS(ISP) 942.4 (M+H)+.
  • 9.7. (6R,7R)-3-[(E)-1-[(S)-1-Allyloxycarbonyl-pyrrolidin-2-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1783, 1685 cm-1
  • MS(ISP) 874.5 (M+H)+.
    • Example 10
  • 10.1. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino] -8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
    Figure 00300001
    To a suspension of (6R,7R)-3-[(E)-(R)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4.12 g, 4.79 mmol) in 280 ml dichloromethane was added 1.87 ml (7.66 mmol) N,O-bis(trimethylsilyl)acetamide whereby an orange solution formed which was subsequently treated with 84 mg (0.12 mmol) bis-(triphenylphosphine)-palladium(II)-dichloride, 5.48 ml (95.8 mmol) acetic acid and 11.7 ml (44.1 mmol) tributyltin hydride and stirred at room temperature for 40 min. After addition of a few drops of water, the suspension was poured on 1500 ml diethylether containing 12 ml of a solution of 6 M hydrogen chloride in diethylether. The suspension was stirred for 2 h and the product was collected by filtration.
  • Yield: 4.04 g (99%) beige solid
  • IR(KBr) 1781, 1659 cm-1
  • MS(ISP) 777.4 (M+H)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 10.2. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(MIR) 1779, 1660 cm-1
  • MS(ISP) 777.4 (M+H)+.
  • 10.3. Mixture of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-(R)- and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1780, 1660 cm-1
  • MS(ISP) 777.3 (M+H)+.
  • 10.4. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[(E)-1-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1780, 1667 cm-1
  • MS(ISP) 763.3 (M+H)+.
  • 10.5. Mixture of (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-(R)- and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add dihydrochloride
  • IR(KBr) 1780, 1659 cm-1
  • MS(ISP) 776.4 (M+H)+.
  • 10.6. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-3-[(E)-1-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1780, 1661 cm-1
  • MS(ISP) 762.5 (M+H)+.
  • 10.7. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-piperidin-4-ylmethyl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1778, 1661, 1631 cm-1
  • MS(ISP) 804.7 (M+H)+.
  • 10.8. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-pyrazolidin-4-yl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride (1:1)
  • m.p. 163-164°C
  • IR(KBr) 1785 cm-1
  • MS(ISP) 778.4 (M+H)+
  • 10.9. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-1-oxo-2-[(3R,4R)-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride (1:2)
  • IR(KBr) 1790, 1633 cm-1
  • MS(ISP) 859.4 (M+H)+.
    • Example 11
  • 11.1. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00320001
    To a solution of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino] -8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride (4.04 g, 4.76 mmol) in 26 ml trifluoroacetic acid was added at 0-5°C 1.69 ml triethylsilane and the mixture was stirred for 30 min. The reaction mixture was poured with stirring on 780 ml ice-cold diethylether upon which the product separated as a beige solid. After stirring for 1 h, the solid was collected by filtration and dried. The product was purified by gel chromatography (MCI Gel 75-150µ, using a gradient of water with increasing concentrations of acetonitrile).
  • Yield: 1.24 g (49%).
  • IR(MIR) 1764, 1658 cm-1
  • MS(ISP) 535.1 (M+H)+.
  • 1H-NMR(DMSO, 250 MHz): inter alia δ 1.92-2.16 (m, 2H); 3.60 (d,J = 17 Hz, 1H); 3.79 (d,J = 17 Hz, 1H); 4.66, (m, 1H); 5.07 (d,J = 8 Hz, 1H); 5.75 (dd,J = 5 Hz, J = 8 Hz 1H); 7.30 (s, 1H); 8.05 (s, 2H); 9.46 (d,J= 8 Hz, 1H); 10.3 (s br, 1H); 12.0 (s br,1H) ppm.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 11.2. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1766, 1687 cm-1
  • MS(ISP) 535.2 (M+H)+.
  • 1H-NMR(DMSO, 250 MHz): inter alia δ 1.92-2.16 (m, 2H); 3.69 (s, 2H); 4.58 (m, 1H), 5.08 (d J = 8 Hz, 1H); 5.75 (dd,J = 5 Hz, J = 8 Hz, 1H); 7.30 (s, 1H); 8.05 (s, 2H); 9.44 (d,J= 8 Hz, 1H); 10 (s br, 1H) ppm.
  • 11.3. Mixture of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)- and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1765, 1659 cm-1
  • MS(ISP) 535.3 (M+H)+.
  • 11.4. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1762, 1689, 1668 cm-1
  • MS(ISP) 521.2 (M+H)+.
  • 11.5. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1766, 1670 cm-1
  • MS(ISP) 534.2 (M+H)+.
  • 11.6. Mixture of (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)- and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1775, 1667 cm-1
  • MS(ISP) 534.3 (M+H)+.
  • 11.7. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
  • IR(KBr) 1776, 1669 cm-1
  • MS(ISP) 520.2 (M+H)+.
  • 11.8. (6R,7R)-7-[(Z)-2(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-piperidin-4-ylmethyl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
  • IR(KBr) 1774, 1664 cm-1
  • MS(ISP) 562.4 (M+H)+.
  • 11.9. 7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-pyrazolidin-4-yl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1756 cm-1
  • MS(ISP) 536.3 (M+H)+.
  • 11.10. (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-pyrazolidin-4-yl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • m.p. 239-240°C
  • IR(KBr) 1764 cm-1
  • MS(ISP) 535.3 (M+H)+.
  • 11.11. (6R,7R)-7-[(Z)- 2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(S)-(2-oxo-1-pyrrolidin-2-ylmethyl-pyrrolidin-3-ylidenemethyl)]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-carboxylic acid
  • IR(KBr) 1785, 1624 cm-1
  • MS(ISP) 549.1 (M+H)+.
  • 11.12. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(S)-(2-oxo-1-pyrrolidin-2-ylmethyl-pyrrolidin-3-ylidenemethyl)]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-carboxylic acid
  • IR(KBr) 1767 cm-1
  • MS(ISP) 548.2 (M+H)+.
  • 11.13. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-[(3R,4R)-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1770, 1665 cm-1
  • MS(ISP) 616.3 (M+H)+.
  • 11.14. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-[(3R,4R)-4-trifluoromethyl-pyrrolidin-3-ylmethyl]-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1768, 1625 cm-1
  • 11.15. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(3'S,5'R)-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1768, 1656 cm-1
  • MS(ISP) 606.1 (M+H)+.
  • 11.16. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(3'S,5'S)-5'dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid formate (1:1)
  • IR(KBr) 1768 cm-1
  • MS(ISP) 606.1 (M+H)+.
  • 11.17. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(3'S,5'R)-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1766, 1656 cm-1
  • MS(ISP) 605.3 (M+H)+.
  • 11.18. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(3'S,5'S)-5'-dimethylcarbamoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1767, 1657 cm-1
  • MS(ISP) 605.1 (M+H)+.
    • Example 12
  • 12.1. Mixture of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-3-[(E)-(R)-and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00350001
    To a suspension of 454 mg (1.19 mmol) (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-cyclopentyloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium salt in 9.5 ml dimethylformamide was added 451 mg (1.19 mmol) O-benzotriazol-1-yl-N,N,N ,N -tetramethyluronium-hexafluorophosphate (HBTU) and the mixture was stirred for 1 h. To the resulting orange solution was added a mixture of (E)-(6R,7R)-3-[(R)- and -[(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethy)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylic acid trifluoroacetate (600 mg, 1.08 mmol) and the mixture was stirred for 40 h at room temperature. The reaction mixture was concentrated in vacuo and the residue distributed between 100 ml ethyl acetate and 70 ml water. The phases were separated and the organic phase was concentrated upon which the product precipitated. The solid was collected by filtration, washed with ethyl acetate and dried, yielding 291 mg (39%) of a beige amorphous powder. Removal of the allyloxycarbonyl-protective group was accomplished according to example 9. The product was purified by gel chromatography (MCI Gel 75-150µ, using a gradient of water with increasing concentrations of acetonitrile).
  • Yield: 40 mg (16%) beige solid
  • IR(KBr) 1771, 1672 cm-1
  • MS(ISP) 603.3 (M+H)+.
  • 12.2. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1777, 1670 cm-1
  • MS(ISP) 603.2 (M+H)+.
    • Example 13
  • 13.1. Mixture of (6R,7R)-3-[(E)-(R)- and -(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00360001
    A suspension of (E)-(6R,7R)-3-[(R)- and [(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (555 mg, 1.0 mmol) in 20 ml DMF was treated for 12 h at room temperature with (Z)-(2-aminothiazol-4-yl)-cyclopentyloxyimino-thioacetic acid S-benzothiazol-2-yl ester (445 mg, 1.1 mmol). The reaction mixture was concentrated in vacuo and the residue triturated in a mixture of 70 ml ethyl acetate and 50 ml water. The solid was collected by filtration, washed with water, ethyl acetate and dried.
  • Yield: 484 mg (71%).
  • IR(KBr) 1778, 1677, 1629 cm-1
  • MS(ISP) 686.4 (M+H)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
  • 13.2 (6R,7R)-3-[(E)-1-(1-Allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1774, 1673 cm-1
  • MS(ISP) 672.4 (M+H)+.
  • 13.3. (6R,7R)-3-[(E)-1-(Allyloxycarbonyl-piperidin-4-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • IR(KBr) 1779, 1676, 1630 cm-1
  • MS(ISP) 714.5 (M+H)+.
    • Example 14
  • 14.1. Mixture of (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-3-[(E)-(R)- and -(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00370001
    Removal of the allyloxycarbonyl-protective group in the mixture of (6R,7R)-3-[(E)-(R)- and -(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acids was accomplished using the procedure described in example 9. The crude product (328 mg) was purified by gel chromatography (MCI Gel 75-150µ, using a gradient of water with increasing concentrations of acetonitrile). The pure product crystallized from the chromatographic fractions and was collected by filtration.
  • Yield: 102 mg (28%) yellow crystals
  • IR(KBr) 1770, 1666, 1625 cm-1
  • MS(ISP) 602.4 (M+H)+.
    • According to the procedure set forth in the preceeding example, the following additional compounds were prepared:
    • 14.2. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-3-(E)-1-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride
    • IR(KBr) 1780, 1661 cm-1
    • MS(ISP) 588.3 (M+H)+.
  • 14.3. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-piperidin-4-ylmethyl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride
  • IR(KBr) 1771, 1665, 1627 cm-1
  • MS(ISP) 630.6 (M+H)+.
    • Example 15
  • (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1'-iminomethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00380001
    To a suspension of 66 mg sodium hydride (65% in mineral oil) in 2 ml DMSO was added 200 mg of ethylformimidate hydrochloride and 100 mg (0.2 mmol) (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The reaction mixture was stirred for 30 min at room temperature before it was hydrolysed with some drops of water. It was purified by reversed-phase chromatography on MCI gel by elution with water: acetonitrile = 9:1.
  • Yield: 30 mg
  • IR(KBr) 1767 cm-1
  • MS(ISP) 562. 2 (M+H)+.
    • Example 16
  • (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-( (R)-1'-carbamimidoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00390001
    To a solution of 150 mg [1,2,4]triazole-1-carboxamidine hydrochloride in 1 ml DMSO were added 13 µl tetramethylguanidine and 53 mg (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. After 1 h stirring at room temperature, the reaction mixture was purified by reversed-phase chromatography on MCI gel by elution with water: acetonitrile = 9:1.
  • Yield: 30 mg
  • IR(KBr) 1769 cm-1
  • MS(ISP) 577.0 (M+H)+.
    • Example 17
    Following the procedures set forth in the above Examples the following compounds can be prepared:
  • 17.1. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)2-hydroxyimino-acetylamino]-3-[(E)-5'-hydroxymethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00390002
  • 17.2. (6R,7R)-3-[(E)-5'-Aminomethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00400001
  • 17.3. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-5'-pyridin-1-ium-1-ylmethyl-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
    Figure 00400002
  • 17.4. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5'-(1-hydroxy-3-methylamino-propyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00400003
  • 17.5. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-4'-hydroxy-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00410001
  • 17.6. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5 -(hydroxy-pyrrolidin-2-yl-methyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00410002
  • 17.7. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-pyrrolidin-3-ylmethyl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00410003
  • 17.8. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00410004
  • 17.9. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1'-azetidin-3-ylmethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00420001
  • 17.10. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1'-pyrrolidin-2-ylmethyl-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00420002
  • 17.11. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(2-hydroxy-ethylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00420003
  • 17.12. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(2-methylamino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00430001
  • 17.13. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(2-cyclopropylamino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00430002
  • 17.14. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(iminomethylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00430003
  • 17.15. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(2-guanidino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00430004
  • 17.16. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-(2-piperazin-1-yl-ethyl)-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00440001
  • 17.17. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-[2-(pyrrolidin-3-ylamino)-ethyl]-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00440002
  • 17.18. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(azetidin-3-ylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00440003
  • 17.19. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-carbamimidoylmethyl-2-oxopyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00450001
  • 17.20. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-iminomethyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00450002
  • 17.21. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-carbamimidoyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00450003
  • 17.22. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-iminomethyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00450004
  • 17.23. (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-carbamimidoyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00460001
  • 17.24. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5'-hydroxymethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00460002
  • 17.25. (6R,7R)-3-[(E)-5'-Aminomethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00460003
  • 17.26. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-5'-pyridin-1-ium-1-ylmethyl-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate
    Figure 00470001
  • 17.27. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5'-(1-hydroxy-3-methylamino-propyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00470002
  • 17.28. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-4'-hydroxy-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00470003
  • 17.29. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5 -(hydroxy-pyrrolidin-2-yl-methyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00470004
  • 17.30. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-pyrrolidin-3-ylmethyl-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00480001
  • 17.31. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2ene-2-carboxylic acid
    Figure 00480002
  • 17.32. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1'-azetidin-3-ylmethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00480003
  • 17.33. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1'-pyrrolidin-2-ylmethyl-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00490001
  • 17.34. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(2-hydroxy-ethylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00490002
  • 17.35. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)- 1-(2-methylamino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00490003
  • 17.36. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)- 1-(2-cyclopropylamino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00490004
  • 17.37. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(iminomethylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00500001
  • 17.38. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(2-guanidino-ethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00500002
  • 17.39. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-(2-piperazin-1-yl-ethyl)-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00500003
  • 17.40. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-2-oxo-1-[2-(pyrrolidin-3-ylamino)-ethyl]-pyrrolidin-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00510001
  • 17.41. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-[2-(azetidin-3-ylamino)-ethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00510002
  • 17.42. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-carbamimidoylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00510003
  • 17.43. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-iminomethyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00510004
  • 17.44. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-carbamimidoyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
    Figure 00520001
  • 17.45. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-iminomethyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add
    Figure 00520002
  • 17.46. (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-(1-carbamimidoyl-azetidin-3-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add
    Figure 00520003

    • Claims (15)

    1. Cephalosporin derivatives of the general formula
      Figure 00530001
      wherein
      X
      is CH or N;
      R1
      is hydrogen or cyclopentyl:
      R2
      is a group of formula
      Figure 00530002
      R3
      is hydrogen, an alkalimetal ion or a tertiary ammonium group;
      R4
      is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl;
      R5
      is hydrogen, dialkylcarbamoyl, ω-hydroxyalkyl, ω-aminoalkyl, pyridinium-1-ylmethyl, 1-hydroxy-3-aminomethyl-propyl or (hydroxy)-(pyrrolidin-2-yl)methyl;
      R6
      is hydrogen, trifluoromethyl or hydroxy; and
      R7
      is alkyl, ω-hydroxy-alkyl, cycloalkyl, 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl;
      as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
    2. Compounds of formula I acdording to claim 1, wherein
      X
      is CH or N;
      R1
      is hydrogen;
      R2
      is a group of formula
      Figure 00540001
      R3
      is hydrogen, an alkalimetal ion or a tertiary ammonium group;
      R4
      is hydrogen, an amino protecting group, iminomethyl, or 1-carbamimidoyl;
      R5
      is hydrogen, hydroxymethyl;
      R6
      is hydrogen or hydroxy; and
      R7
      methyl or 2-hydroxyethyl;
      as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
    3. Compounds of formula I according to claim 1 or 2, wherein X is CH or N; and R2 respresents a group of the formula
      Figure 00550001
         wherein R4 is hydrogen, iminomethyl or 1-carbamimidoyl; R5 is hydrogen or hydroxymethyl; and R6 is hydrogen or hydroxy.
    4. Compounds of formula I according to claim 1 or 2, wherein X is CH or N and R2 represents a group of the formula
      Figure 00550002
         wherein R4 is hydrogen, iminomethyl or 1-carbamimidoyl; R5 is hydrogen or hydroxymethyl; and R6 is hydrogen or hydroxy.
    5. Compounds of formula I according to anyone of claims 1 to 4, wherein R5 and R6 are hydrogen.
    6. Compounds of formula I according to anyone of claims 1 to 5, wherein the pyrrolidinone is in the E-form.
    7. Compounds of formula I according to claim 2, wherein X is CH and R2 is a group of formula
      Figure 00550003
         wherein R4 is as defined in claim 2.
    8. Compounds of formula I according to claim 2, wherein X is N and R2 is a group of formula
      Figure 00550004
         wherein R4 is as defined in claim 2.
    9. Compounds of formula I according to claim 1, wherein
      X
      is CH or N;
      R1
      is hydrogen or cyclopentyl;
      R2
      is a group of formula
      Figure 00560001
      R3
      is hydrogen, an alkalimetal ion or a tertiary ammonium group;
      R4
      is hydrogen, an amino protecting group;
      R5
      is hydrogen, dialkylcarbamoyl; and
      R6
      is hydrogen or trifluoromethyl;
      as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
    10. The compounds
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1'-iminomethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-( (R)-1'-carbamimidoyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-1-azetidin-3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
      (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-5'-hydroxymethyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
    11. Compounds as in any one of claims 1 to 10 for use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases.
    12. Process for the manufacture of compounds of formula I, which process comprises treating a compound having the formula II
      Figure 00570001
         in which R2 is defined as in claim 1, or an ester or a salt thereof, the amino group and the carboxylic groups present the compound of formula II may be unprotected or protected,
      with a carboxylic acid of the general formula III
      Figure 00570002
         in which Rf is hydrogen or an amino protecting group, R1' is hydrogen, cyclopentyl or a hydroxy protecting group and X is as defined above, or a reactive functional derivative thereof, or
      (b) cleaving off the amino, hydroxy and/or carboxy protecting group in a compound having the formula IV
      Figure 00580001
         in which R2 is as defined above, Rf is hydrogen or an amino protecting group, R1'' is hydrogen or a hydroxy protecting group, Rh is hydrogen or a carboxy protecting group, provided that at least one of Rf , R1'' and Rh is a corresponding protecting group,
      or a salt thereof.
    13. The compound of formula IIIa (Z)-(5-Amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester.
    14. A pharmaceutical preparation containing a compound according to any one of claims 1 to 10 and a therapeutically inert carrier, particularly for the treatment and prophylaxis of infectious diseases.
    15. The use of the compounds according to any one of claims 1 to 10 in the treatment and prophylaxis of infectious diseases or for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.
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    US5977381A (en) * 1998-01-12 1999-11-02 Hoffmann-La Roche Inc. Process for making 3-amino-pyrolidine derivatives
    WO1999065920A1 (en) * 1998-06-15 1999-12-23 F. Hoffmann-La Roche Ag Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems
    US6232306B1 (en) 1998-06-15 2001-05-15 Hoffmann-La Roche Inc. Derivatives of 3-(2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl)-cephams
    WO2000032605A1 (en) * 1998-12-03 2000-06-08 F. Hoffmann-La Roche Ag Bi-pyrrolidinylvinl (carba) cephalosporins
    EP1067131A1 (en) * 1999-07-05 2001-01-10 F. Hoffmann-La Roche Ag New process for the manufacture of cephalosporin derivatives
    US6384214B1 (en) 1999-07-05 2002-05-07 Basilea Pharmaceutica Ag Process for producing cephalosporin derivatives
    WO2001004127A1 (en) * 1999-07-07 2001-01-18 F. Hoffmann-La Roche Ag Vinylpyrrolidinone derivatives with substituted thiazole ring
    US6420166B2 (en) 2000-04-19 2002-07-16 Basolea Pharmaceutica Ag Process for the preparation of D-asparagine derivatives
    CN1915997B (en) * 2000-05-24 2010-06-16 巴斯利尔药物股份公司 New process for the preparation of vinyl-pyrrolidone cephalosporin derivatives
    US6504025B2 (en) 2000-05-24 2003-01-07 Basilea Pharmaceutica Ag Process for the preparation of vinyl-pyrrolidinone cephalosporin derivatives
    WO2001090111A1 (en) * 2000-05-24 2001-11-29 Basilea Pharmaceutica Ag New process for the preparation of vinyl-pyrrolidinone cephalosporine derivatives
    EP1435357A3 (en) * 2000-05-24 2006-05-03 Basilea Pharmaceutica AG New process for the preparation of vinyl-pyrrolidinone cephalosporine derivatives
    CN1301998C (en) * 2000-05-24 2007-02-28 巴斯利尔药物股份公司 Method for preparing vinyl-pyrrolidone cephalosporin derivatives
    US7511154B2 (en) 2000-08-14 2009-03-31 Basilea Pharmaceuticals Ag Preparation of N-protected-3-pyrrolidine-lactam substituted phosphonium salts
    US6828442B2 (en) 2000-08-14 2004-12-07 Basilea Pharmaceutica Ag Preparation of n-protected-3-pyrrolidine-lactam substituted phosphonium salts
    WO2002014332A1 (en) * 2000-08-14 2002-02-21 Basilea Pharmaceutica Ag Preparation of n-protected-3-pyrrolidine-lactam substituted phosphonium salts
    US7262307B2 (en) 2000-08-14 2007-08-28 Basilea Pharmaceutica Ag 1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one
    CN1309713C (en) * 2001-11-09 2007-04-11 安蒂比奥蒂科斯有限公司 A process for the preparation of cephalosporins side chains
    WO2003040116A1 (en) * 2001-11-09 2003-05-15 Antibioticos S.P.A. A process for the preparation of cephalosporins side chains
    US7531650B2 (en) 2003-03-27 2009-05-12 Basilea Pharmaceutica Ag Cephalosporin salts in crystalline form
    US8445476B2 (en) 2007-10-25 2013-05-21 Achaogen, Inc. Carbacephem β-lactam antibiotics
    US9163034B2 (en) 2008-04-15 2015-10-20 Basilea Pharmaceutica Ag Crystalline (6R,7R)-7-{2-(5-amino-[1,2,4] thiadiazol-3-yl)-2-[(Z)-trityloxyimino]-acetylamino}-3-[(R)-1′-tert-butoxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-(3E)-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester; its manufacture and use
    US8865697B2 (en) 2008-04-15 2014-10-21 Basilea Pharmaceutica Ag Crystalline (6R,7R)-7-{2-(5-amino-[1,2,4] thiadiazol-3-yl)-2-[(Z)-trityloxyimino]-acetylamino}-3-[(R)-1′-tert-butoxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-(3E)-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester; its manufacture and use
    WO2010030810A1 (en) * 2008-09-10 2010-03-18 Achaogen, Inc. Carbacephem beta-lactam antibiotics
    WO2010072672A1 (en) 2008-12-24 2010-07-01 Basilea Pharmaceutica Ag New crystal polymorphs of ceftobiprole
    US20120116070A1 (en) * 2009-05-25 2012-05-10 Sandoz Ag Method for the production of ceftobiprole medocaril
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    EP0849269B1 (en) 2002-07-10
    ATE220402T1 (en) 2002-07-15
    KR19980064240A (en) 1998-10-07
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    KR100310384B1 (en) 2001-11-08
    ES2179996T3 (en) 2003-02-01
    MA26457A1 (en) 2004-12-20
    AU4846397A (en) 1998-06-25
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    IL122604A0 (en) 1998-08-16
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    CN1347883A (en) 2002-05-08
    CN1104436C (en) 2003-04-02
    DE69713865D1 (en) 2002-08-14
    HUP9702474A2 (en) 1998-11-30
    EP0849269B9 (en) 2003-03-05
    CZ405797A3 (en) 1998-07-15
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    CN1325850A (en) 2001-12-12
    CA2224438A1 (en) 1998-06-19
    PT849269E (en) 2002-11-29
    NO975901L (en) 1998-06-22
    KR100395985B1 (en) 2004-02-14
    US5981519A (en) 1999-11-09
    JP2002060390A (en) 2002-02-26
    CN1183141C (en) 2005-01-05
    CY2400B1 (en) 2004-09-10
    JP3264877B2 (en) 2002-03-11
    CA2224438C (en) 2009-02-24
    CA2628224A1 (en) 1998-06-19
    CA2628224C (en) 2010-02-16
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    DK0849269T3 (en) 2002-10-28
    DE69713865T2 (en) 2003-02-20
    AU729653B2 (en) 2001-02-08
    CN1163496C (en) 2004-08-25
    TW415949B (en) 2000-12-21
    JP4043203B2 (en) 2008-02-06
    NZ329363A (en) 1999-01-28
    NO975901D0 (en) 1997-12-16
    CN1132833C (en) 2003-12-31
    CN1347884A (en) 2002-05-08
    CN1188112A (en) 1998-07-22

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